Substituted pyrido-or pyrimido-containing 6,6- or 6,7-bicyclic derivatives

ABSTRACT

This invention relates to compounds of formula (I), wherein A, B, D, E, K, G, Z, R 3  and R 5  are defined as in the specification, and to the pharmaceutically acceptable salts of such compounds. Compounds (I) are corticotropin releasing factor (hormone) CRF (CRH) antagonists.

This application claims the benefit of U.S. provisional Application No.60/023,453 filed Aug. 6, 1996.

BACKGROUND OF THE INVENTION

This invention relates to certain pharmaceutically active substitutedpyrido- or pyrimido-containing 6,6- or 6,7-bicyclic derivatives,pharmaceutical compositions containing them and methods of administeringthem to subjects in need of their corticotropin releasing factorantagonist activity.

The substituted heterocyclic derivatives claimed in this case exhibitactivity as corticotropin releasing factor (hormone) CRF (CRH)antagonists.

CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245referring to peptides and pyrazolinones, respectively. They are alsoreferred to in the following: PCT Patent Application PCT/IB95/00439,which designates the United States and was filed on Jun. 6, 1995 andpublished on Dec. 14, 1995; PCT patent application PCT/IB95/00373, whichdesignates the United States and was filed on May 18, 1995 and publishedon Dec. 21, 1995; U.S. patent application Ser. No. 08/448,539, which wasfiled in the PCT on Nov. 12, 1993 and entered the U.S. national phase onJun. 14, 1995; PCT patent application WO 95/10506, which was filed onOct. 12, 1993 and published on Apr. 20, 1995, and U.S. patentapplication 08/481,413, which was filed in the PCT on Nov. 26, 1993 andentered the U.S. national phase on Jul. 24, 1995; U.S. patentapplication Ser. No. 08/254,820, which was filed on Apr. 19, 1995;Provisional U.S. patent application Ser. No. 60/008,396, which was filedon Dec. 8, 1995; and Provisional U.S. patent application Ser. No.60/006,333, which was filed on Nov. 8, 1995. All the foregoing patentapplications are incorporated herein by reference in their entireties.

The importance of CRF antagonists is set out in the literature, e.g., P.Black, Scientific American SCIENCE & MEDICINE, 1995, p. 16-25; T.Lovenberg, et al., Current Pharmaceutical Design, 1995, 1, 305-316; andU.S. Pat. No. 5,063,245, which is referred to above. A recent outline ofthe different activities possessed by CRF antagonists is found in M. J.Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), alsoincorporated herein by reference. Based on the research described inthese two and other references, CRF antagonists are effective in thetreatment of a wide range of stress-related Illnesses, mood disorderssuch as depression, major depressive disorder, single episodedepression, recurrent depression, child abuse induced depression,postpartum depression, dysthemia, bipolar disorders and cyclothymia;chronic fatigue syndrome; eating disorders such as anorexia and bulimianervosa; generalized anxiety disorder; panic disorder; phobias;obsessive-compulsive disorder, post-traumatic stress disorder, painperception such as fibromyalgia; headache; gastrointestinal diseases;hemorrhagic stress; ulcers; stress-induced psychotic episodes; fever;diarrhea; post-operative ileus, colonic hypersensitivity; irritablebowel syndrome; Crohn's disease; spastic colon; inflammatory disorderssuch as rheumatoid arthritis and osteoarthritis; pain; asthma;psoriasis; allergies; osteoporosis; premature birth; hypertension,congestive heart failure; sleep disorders; neurodegenerative diseasessuch as Alzheimers disease, senile dementia of the Alzheimer's type,multiinfarct dementia, Parkinson's disease, and Huntington's disease;head trauma; ischemic neuronal damage; excitotoxic neuronal damage;epilepsy; stroke; spinal cord trauma; psychosocial dwarfism; euthyroidsick syndrome; syndrome of inappropriate antidiarrhetic hormone;obesity; chemical dependencies and addictions; drug and alcoholwithdrawal symptoms; infertility, cancer; infertility; muscular spasms;urinary incontinence; hypoglycemia and immune dysfunctions includingstress induced immune dysfunctions, immune suppression and humanimmunodeficiency virus infections; and stress-induced infections inhumans and animals.

The compounds of this invention are also believed to be inhibitors ofCRH binding protein and therefore useful in the treatment of disordersthe treatment of which can be effected or facilitated by inhibiting suchprotein. Example of such disorders are Alheimer's disease and obesity.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula

the dashed lines represent optional double bonds;

A is nitrogen or CR⁷:

B is —NR¹R², —CR¹R²R¹⁰, —C(═CR²R¹¹)R¹, —NHCR¹R²R¹⁰, —OCR¹R²R¹⁰,—SCR¹R²R¹⁰, —CR²R¹⁰NHR¹, —CR²R¹⁰OR¹, —CR²R¹⁰SR¹ or —COR², and is singlebonded to D; or B is —CR¹R², and is double bonded to D and D is carbon;

D is nitrogen or CR⁴ and is single bonded to all atoms to which it isattached, or D is carbon and is double bonded to E or double bonded toB;

E is oxygen, nitrogen, sulfur, C═O, C═S, CR⁶R¹², NR⁶ or CR⁶; or E is atwo atom spacer, wherein one of the atoms is oxygen, nitrogen, sulfur,C═O, C═S, CR⁶R¹², NR⁶ or CR⁶, and the other is CR⁶R¹² or CR⁹;

K and G are each, independently, C═O, C═S, sulfur, oxygen, CHR⁸ or NR⁸when single bonded to both adjacent ring atoms, or nitrogen or CR⁸ whenit is double bonded to an adjacent ring atom;

the 6- or 7-membered ring that contains D, E, K and G may contain fromone to three double bonds, from zero to two heteroatoms selected fromoxygen, nitrogen and sulfur, and from zero to two C═O or C═S groups,wherein the carbon atoms of such groups are part of the ring and theoxygen and sulfur atoms are substituents on the ring;

R¹ is C₁-C₆ alkyl optionally substituted with from one or twosubstituents independently selected from hydroxy, fluoro, chloro, bromo,iodo, C₁-C₄ alkoxy, CF₃, —C(═O)(C₁-C₄alkyl), —C(═O)—O—(C₁-C₄)alkyl,—OC(═O)(C₁-C₄ alkyl), —OC(═O)N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —NHCO(C₁-C₄alkyl), —COOH, —COO(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄alkyl)(C₁-C₂ alkyl), —S(C₁-C₄ alkyl), —CN, —NO₂, —SO(C₁-C₄ alkyl),—SO₂(C₄ alkyl), —SO₂NH(C₁-C₄ alkyl) and —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl),wherein each of the C₁-C₄ alkyl groups in the foregoing R¹ groups mayoptionally contain one or two double or triple bonds;

R² is C₁-C₁₂ alkyl which may optionally contain from one to three doubleor triple bonds, aryl or (C₁-C₄ alkylene)aryl, wherein said aryl and thearyl moiety of said (C₁-C₄ alkylene)aryl is selected from phenyl,naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl andbenzoxazolyl; C₃-C₈ cycloalkyl or (C₁-C₆ alkylene)(C₃-C₈ cycloalkyl),wherein one or two of the carbon atoms of said cycloalkyl and the 5 to 8membered cycloalkyl moieties of said (C₁-C₆ alkylene)(C₃-C₈ cycloalkylmay optionally and independently be replaced by an oxygen or sulfur andwherein each of the foregoing R² groups may optionally be substitutedwith from one to three substituents independently selected from chloro,fluoro, hydroxy and C₁-C₄ alkyl, or with one substituent selected fromC₁-C₆ alkoxy, —OC(═O)(C₁-C₆ alkyl), —OC(═O)N(C₁-C₄ alkyl)(C₁-C₂ alkyl),—S(C₁-C₆ alkyl), amino, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)—CO—(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl), —COOH, —COO(C₁-C₄alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SH, —CN,—NO₂, —SO(C₁-C₄ alkyl), —SO₂(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkyl) and—SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl);

—NR¹R² or CR¹R²R¹⁰ may form a ring selected from saturated 3 to 8membered rings, the 5 to 8 membered rings of which may optionallycontain one or two double bonds, and wherein one or two of the ringcarbon atoms of such 5 to 8 membered rings may optionally andindependently be replaced by an oxygen or sulfur atom or by NZ³ whereinZ³ is hydrogen or C₁-C₄ alkyl;

R³ is hydrogen, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), chloro, fluoro, bromo,iodo, —S(C₁-C₄ alkyl) or —SO₂(C₁-C₄ alkyl)

R⁴ is hydrogen, C₁-C₂ alkyl, hydroxy or fluoro;

each R⁶, R⁸ and R⁹ that is attached to a carbon atom is selected,independently, from hydrogen, C₁-C₂ alkyl, fluoro, chloro, bromo, iodo,hydroxy, hydroxymethyl, formyl, trifluoromethyl, cyano, amino, nitro,—O(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)(C₁-C₂ alkyl), —S(C₁-C₂ alkyl),—CO(C₁-C₂ alkyl), —C(═O)H or —C(═O)O(C₁-C₂ alkyl), wherein each of theC₁-C₂ alkyl moieties in the foregoing R⁶, R⁸, and R⁹ groups mayoptionally contain one double or triple bond; and each R⁶, R⁸, and R⁹that is attached to a nitrogen atom is selected, independently, fromhydrogen and C₁-C₄ alkyl;

R⁵ is substituted phenyl, naphthyl, pyridyl or pyrimidyl, wherein eachof the foregoing R⁵ groups is substituted with from two to foursubstituents R¹⁵, wherein from one to three of said substituents may beselected, independently, from chloro, C₁-C₆ alkyl, —O(C₁-C₆ alkyl) and—(C₁-C₆ alkylene)O(C₁-C₆ alkyl), and wherein one of said substituentsmay be selected, independently, from bromo, iodo, formyl, cyano,trifluoromethyl, nitro, amino, —NH(C₁-C₄ alkyl), —N(C₁-C₂ alkyl)(C₁-C₅alkyl), —C(═O)O(C₁-C₄ alkyl), —C(═O)(C₁-C₄ alkyl), —COOH, —SO₂NH(C₁-C₄alkyl), —SO₂N(C₁-C₂ alkyl)(C₁-C₄ alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl),—S(C₁-C₆ alkyl) and —SO₂(C₁-C₆ alkyl), and wherein each of the C₁-C₄alkyl and C₁-C₆ alkyl moieties in the foregoing R⁵ groups may optionallybe substituted with one or two substituents independently selected fromfluoro, hydroxy, amino, methylamino, dimethylamino and acetyl;

R⁷ is hydrogen, methyl, halo (e.g., chloro, fluoro, lodo or bromo),hydroxy, methoxy, —C(═O)(C₁-C₂ alkyl), —C(═O)O(C₁-C₂ alkyl),trifluoromethoxy, hydroxymethyl, trifluoromethyl, or formyl;

R¹⁰ is hydrogen, hydroxy, methoxy or fluoro;

R¹¹ is hydrogen or C₁-C₄ alkyl;

R¹² is hydrogen or methyl; and

Z is NH, oxygen, sulfur, —N(C₁-C₄ alkyl), or CR¹³R¹⁴ wherein R¹³ and R¹⁴are independently selected from hydrogen, and methyl with the exceptionthat one of R¹³ and R¹⁴ may optionally be cyano;

with the proviso that: (a) in the six or seven membered rings ofstructures in formula I, there can not be two double bonds adjacent toeach other; and (b) when D is carbon and is double bonded to B, then Bis CR¹R²;

and the pharmaceutically acceptable salts of such compounds.

Examples of more specific embodiments of formula I are the following,wherein (R)n represents from zero to two substituents, wherein suchsubstitutents are as defined above in the definition of formula 1.

More specific embodiments of this invention include compounds of theformula I wherein B is —CHR¹R² or —NR¹R², and R¹ is C₁-C₆ alkyl whichmay optionally be substituted with one hydroxy, fluoro, trifluoromethylor C₁-C₄ alkoxy group and may optionally contain one double or triplebond; and R² is benzyl or C₁-C₆ alkyl which may optionally contain onedouble or triple bond, and wherein said C₁-C₆ alkyl and the phenylmoiety of said benzyl may optionally be substituted with one fluoro,C₁-C₂ alkyl, C₁-C₂ alkoxy or chloro group.

Other more specific embodiments of the invention include compounds offormula I wherein R³ is methyl, ethyl, chloro or methoxy; R⁶, R⁸ and R⁹are selected, independently, from hydrogen and methyl; R⁵ is di- ortri-substituted phenyl, pyridyl, or pyrimidyl, in which up to three ofthe substitutents can be independently selected from C-C₄ alkyl,—O—(C₁-C₄ alkyl) and (C₁-C₂ alkylene)—O—(C₁-C₄ alkyl), and wherein oneof the substituents can be independently selected from trifluoromethyl,trifluoromethoxy, —CHO, (C₁-C₄ alkyl)—OH, cyano, chloro, fluoro, bromo,iodo and nitro, and wherein each of the foregoing (C₁-C₄) alkyl groupsmay optionally contain one double or triple bond; and Z is oxygen or NH.

Other more specific embodiments of the invention include compounds ofthe formula I wherein A is nitrogen or CH.

Examples of preferred compounds of the invention are:

1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;

1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylicacid methyl ester;

1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylicacid isopropyl ester;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;

1-(1-ethyl-propyl)-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6]-naphthyridin-2-one;and

1-(1-ethyl-propyl)-3,3,6-trimethyl-4-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine.

Other compounds of the formula I include the following:

1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;

1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;

1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylicacid methyl ester;

1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylicacid isopropyl ester;

1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine;

1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6diaza-naphthalene;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;

1-(1-ethyl-propyl)-3,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6]-naphthyridin-2-one;

1-(1-ethyl-propyl)-3,3,6-trimethyl-4-(4-bromo-2,6-dimethyl-phenoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;

1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;

1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylicacid methyl ester;

1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylicacid isopropyl ester;

1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-.tetrahydro[1,6]naphthyridine;

1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;

1-(1-ethyl-propyl)-3,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6-naphthyridin-2-one;

1-(1-ethyl-propyl)-3,3,6-trimethyl-4-(4-chloro-2,6-dimethyl-phenoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine;

[1-(1-ethyl-propyl)-7-methyl-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-(1-ethyl-propyl)-7-methyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-y-(2,4,6-trimethyl-phenyl)-amine;

3-[7-methyl-5-(2,4,6-trimethyl-phenoxy)-4H-3-oxa-1,6-diaza-naphthalen-1-yl]-pentan-1-ol;2-[7-methyl-5-(2,4,6-trimethyl-phenoxy)-4H-3-oxa-1,6-diaza-naphthalen-1-yl]-butan-1-ol;

1-(1-ethyl-butyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;

7-methyl-1-(1-propyl-butyl)-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenylamino)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;

8-(1-ethyl-propyl)-2-methyl4-(2,4,6-trimethyl-phenylamino)-7,8-dihydro-5H-pyridin-6-one;

8-(1-ethyl-propyl)-2-methyl-4-(2,4,6trimethyl-phenoxy)-7,8-dihydro-5H-pyridin-6-one;

8-(1-ethyl-propyl)-2-methyl-4-(2,4,6-trimethyl-phenoxy)-5,6,7,8-tetrahydro-pyridine;

[8-(1-ethyl-propyl)-2-methyl-5,6,7,8-tetrahydro-pyridin-4-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;8-(1-ethyl-propyl)-2-methyl-4-(2,4,6-trimethyl-phenoxy)-5,6,7,8-tetrahydro-pyridine;

[8-(1-ethyl-propyl)-2-methyl-5,6,7,8-tetrahydro-pyridin-4-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-[1,6]naphthyridinin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

8-(1-ethyl-propyl)-2-methyl-4-(2,4,6-trimethyl-phenoxy)-5,6,7,8-tetrahydro-pyrido(2,3d]pyrimidine;

[8-(1-ethyl-propyl)-2-methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4yl]-(2,4,6-trimethyl-phenyl)-amine;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine;

[1-(1-ethyl-propyl)-4,7-dimethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-(1-ethyl-propyl)-4,7-dimethyl-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

1-(1-hydroxymethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;

1-(1-hydroxymethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;

2-[4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-2H-pyrido[3,4-b]pyrazin-1-yl]-butan-1-ol;

2-[7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-2H-pyrido[3,4-b]pyrazin-1-yl]-butan-1-ol;

2-[7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-2H-[1,6]naphthyridin-1-yl]-butan-1-ol;

2-[4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)4H-3-oxa-1,6-diaza-naphthalen-1-yl]-butan-1-ol;

5-(1-ethyl-propyl)-3-methyl-1-(2,4,6-trimethyl-phenoxy)-isoquinoline;

diethyl-[3-methyl-1-(2,4,6-trimethyl-phenoxy)-isoquinolin-5-yl]-amine;

[5-(1-ethyl-propyl)-3-methyl-isoquinolin-1-yl]-(2,4,6-trimethyl-phenyl)-amine;

N-5-butyl-N-5-ethyl-3-methyl-N1-(2,4,6-trimethyl-phenyl)-isoquinoline-1,5-diamine;

5-(1-ethyl-propyl)-3-methyl-1-(2,4,6-trimethyl-phenoxy)-[2,6]naphthyridine;

5(1-ethyl-propyl)-3-methyl-1-(2,4,6-tnimethyl-phenoxy)-[2,7]naphthyridine;

4-(1-ethyl-propyl)-6-methyl-8-(2,4,6-trimethyl-phenoxy)-[1,7]naphthyridine;

[5-(1-ethyl-propyl)-3-methyl-[2,6]naphthyridin-1-yl]-(2,4,6-trimethyl-phenyl)-amine;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenylamino-1H-[1,6]naphthyridin-2-one;

4-(1-ethyl-propyl)-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;

4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;

4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalene;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-thia-1,6-diaza-naphthalene;

[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-[1,6]naphthyridin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-(1-ethyl-propyl)-7-methyl-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-(1-ethyl-propyl)-7-methyl-2,3-dihydro-1H4-thia-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;

1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[4,3-d]pyrimidine;

1-(1-ethyl-propyl)-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[4,3-d]pyrimidine;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridinetetrahydro-pyrido[4,3-d]pyrimidine;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;

1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[4,3-d]pyrimidine;

4-(1-ethyl-propyl)-6-methyl-8-(2,4-trimethyl-phenoxy)-pyrano[2,3-c]pyridin-2-one;

1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;

1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]3naphthyridine;

1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;

1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;

1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4dihydro-2H-3-ixa-1,6-diaza-napthalene;

1-sec-butyl4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-]pyrazine;

7-methyl-1-(1-propyl-butyl)-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine;

5-sec-butyl-3-methyl-1-(2,4,6trimethyi-phenoxy)-isoquinoline;

diethyl-[3-methyl-1-(2,4,6-trimethyl-phenoxy)-isoquinolin-5-yl]-amine;

[5-sec-butyl-3-methyl-isoquinolin-1-yl]-(2,4,6-trimethyl-phenyl)-amine;

N-5-butyl-N-ethyl-3methyl-N1-(2,4,6-trimethyl-phenyl)-isoquinoline-1,5diamine;

5-sec-butyl-3-methyl-1-(2,4,6-trimethyl-phenoxy)-[2,61naphthyeidine;

5-sec-butyl-3-methyl-1-(2,4,6-trimethyl-phenoxy)-[2,7]naphthyridine;

4-sec-butyl-6-methyl-8-(2,4,6-trimethyl-phenoxy)-[1,7]naphthyridine;

[5-sec-butyl-3-methyl-[2,6]naphthyridin-1-yl]-(2,4,6trimethyl-phenyl)-amine;

1-sec-butyl-7-methyl-5-(2,4,6tnimethyl-phenylamino)-1H-[1,6]naphthyridin-2-one;

4-sec-butyl-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;

4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;

4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;

1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;

1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalene;

1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-thia-1,6-diaza-naphthalene;

[1-sec-butyl-7-methyl-1,2,3,4-tetrahydro-[1,6]naphthyridin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-sec-butyl-7-methyl-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6trimethyl-phenyl)-amine;

[1-sec-butyl-7-methyl-2,3-dihydro-1H-4-thia-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-sec-butyl-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

[1-sec-butyl-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;

1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;

1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido-[4,3-d]pyrimidine;

1-sec-butyl-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido-[4,-d]pyrimidine;

1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]-naphthyridinetetrahydro-pyrido[4,3-d]pyrimidine;

1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;

1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4tetrahydro-pyrido-[4,3-d]pyrimidine;and

4-sec-butyl-6-methyl-8-(2,4,6-trimethyl-phenoxy)-pyrano[2,3-c]pyridin-2-one.

Unless otherwise indicated, the alkyl groups referred to herein, as wellas the alkyl moieties of other groups referred to herein (e.g., alkoxy),may be linear or branched, and they may also be cyclic (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear orbranched and contain cyclic moieties.

The invention also relates to a pharmaceutical composition for thetreatment, prevention or inhibition of (a) a disorder the treatment ofwhich can be effected or facilitated by antagonizing CRF, including butnot limited to disorders induced or facilitated by CRF, or (b) adisorder selected from inflammatory disorders such as rheumatoidarthritis and osteoarthritis, pain, asthma, psoriasis and allergies;generalized anxiety disorder; panic; phobias; obsessive-compulsivedisorder; post-traumatic stress disorder; sleep disorders induced bystress; pain perception such as fibromyalgia;

mood disorders such as depression, including major depression, singleepisode depression, recurrent depression, child abuse induceddepression, mood disorders associated with premenstrual syndrome, andpostpartum depression; dysthemia; bipolar disorders; cyclothymia;chronic fatigue syndrome; stress-induced headache; cancer; irritablebowel syndrome, Crohn's disease; spastic colon; post operative ileus;ulcer; diarrhea; stress-induced fever; human immunodeficiency virus(HIV) infections; neurodegenerative diseases such as Alzheimers disease,Parkinson's disease and

Huntington's disease; gastrointestinal diseases; eating disorders suchas anorexia and bulimia nervosa; hemorrhagic stress; chemicaldependencies and addictions (e.g., dependencies on alcohol, nicotine,cocaine, heroin, benzodiazepines, or other drugs); drug and alcoholwithdrawal symptoms; stress-induced psychotic episodes; euthyroid sicksyndrome; syndrome of inappropriate antidiarrhetic hormone (ADH);obesity; infertility; head traumas; spinal cord trauma; ischemicneuronal damage (e.g., cerebral ischemia such as cerebral hippocampalischemia); excitotoxic neuronal damage; epilepsy; stroke; immunedysfunctions including stress induced immune dysfunctions (e.g., porcinestress syndrome, bovine shipping fever, equine paroxysmal fibrillation,and dysfunctions induced by confinement in chickens, sheering stress insheep or human-animal interaction related stress in dogs); muscularspasms; urinary incontinence; senile dementia of the Alzheimer's type;multiinfarct dementia; amyotrophic lateral sclerosis; hypertension;tachycardia; congestive heart failure; osteoporosis; premature birth;and hypoglycemia in a mammal, including a human, comprising an amount ofa compound of the formula I or a pharmaceutically acceptable saltthereof, that is effective in the treatment of such disorder, and apharmaceutically acceptable carrier.

The invention also relates to a method for the treatment, prevention orinhibition of (a) a disorder the treatment of which can be effected orfacilitated by antagonizing CRF, including but not limited to disordersinduced or facilitator by CRF, or (b) a disorder selected frominflammatory disorders such as rheumatoid arthritis and osteoarthritis,pain, asthma, psoriasis and allergies; generalized anxiety disorder;panic; phobias; obsessive-compulsive disorder; post-traumatic stressdisorder; sleep disorders induced by stress; pain perception such asfibromyalgia; mood disorders such as depression, including majordepression, single episode depression, recurrent depression, child abuseinduced depression, mood disorders associated with premenstrualsyndrome, and postpartum depression; dysthemia; bipolar disorders;cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer;irritable bowel syndrome; Crohn's disease; spastic colon; post operativeileus; ulcer; diarrhea; stress-induced fever; human immunodeficiencyvirus (HIV) infections; neurodegenerative diseases such as Alzheimer'sdisease, Parkinson's disease and Huntington's disease; gastrointestinaldiseases; eating disorders such as anorexia and bulimia nervosa;hemorrhagic stress; stress-induced psychotic episodes; euthyroid sicksyndrome; syndrome of inappropriate antidiarrhetic hormone (ADH);obesity; infertility; head traumas; spinal cord trauma; ischemicneuronal damage (e.g., cerebral ischemia such as cerebral hippocampalischemia); excitotoxic neuronal damage; epilepsy; stroke; immunedysfunctions including stress induced immune dysfunctions (e.g., porcinestress syndrome, bovine shipping fever, equine paroxysmal fibrillation,and dysfunctions induced by confinement in chickens, sheering stress insheep or human-animal interaction related stress in dogs); muscularspasms; urinary incontinence; senile dementia of the Alzheimers type;multiinfarct dementia; amyotrophic lateral sclerosis; chemicaldependencies and addictions (e.g., dependencies on alcohol, nicotine,cocaine, heroin, benzodiazepines, or other drugs); drug and alcoholwithdrawal symptoms; hypertension; tachycardia; congestive heartfailure; osteoporosis; premature birth; and hypoglycemia in a mammal,including a human, comprising administering to a subject in need of saidtreatment an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disorder.

This invention also relates to a method of treating or preventing adisorder or condition, the treatment or prevention of which can beeffected or facilitated by inhibiting CRH binding protein in a mammal,including a human, comprising administering to said mammal a CRH bindingprotein inhibiting amount of a compound of the formula I or apharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition for treatingor preventing a disorder or condition, the treatment or prevention ofwhich can be effected or facilitated by inhibiting CRH binding proteinin a mammal, including a human, comprising a CRH binding proteininhibiting amount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention further includes intermediate compounds of formulas

a wherein T is chloro, bromo, iodo, or —OSO₂CF₃; U is CN, —COO(C₁-C₄alkyl), chloro, bromo, iodo, —OSO₂CF₃, hydroxy or amino when D iscarbon, and U is hydrogen when D is nitrogen.

This invention includes all optical isomers and other stereoisomers ofcompounds of the formula I. When such compounds contain one or morechiral centers, it is understood that the invention includes the racemicmixtures as well as all individual enantiomers and diastereomers of suchcompounds, and mixtures thereof.

The compounds of this invention include compounds identical to thosedescribed above but for the fact that one or more hydrogen, nitrogen orcarbon atoms are replaced by isotopes thereof (e.g., tritium orcarbon-14 isotopes). Such compounds are useful as research anddiagnostic tools in metabolism pharmokinetic studies and in bindingassays.

DETAILED DESCRIPTION OF THE INVENTION

The following compounds having the formulas II, III, and IV are usefulas intermediates in the synthesis of compounds of the formula I.

In the above compounds of formulas II to IV, M is chloro, bromo, iodo,—OSO₂CF₃ or ZR⁵; P is NH, CHCN or CHCOO(C₁-C₄ alkyl); Q is amino,—(C₁-C₂ alkyl)CH[COO(C₁-c₄alkyl)]₂, (C₂-C₃ alkyl)-CN, hydroxy ormercapto, and A, B, D, E, K and G are defined as above.

Methods of preparing the compounds and compositions of this inventionare described below. In the discussion and reaction schemes that follow,R¹ through R¹⁴, R¹², A, B, D, E, K, G. Z, T, M, P, Q, and U, the dashedlines and structural formulas I, II, III, and IV, unless otherwiseindicated, are defined as above.

Compounds of the formula I may be prepared by reacting a compound of theformula 11 with the corresponding compound of the formula R⁵ZH. Thisreaction is generally carried out with or without a solvent, in thepresence of a base, at a temperature from about 0° C. to about 270° C.,at a pressure from about 14 psi to about 300 psi. Suitable solventsinclude organic solvents such as tetrahydrofuran (THF), acetonitrile,N,N-dimethylformamide (DMF), dimethylsulfoxide (DMS0), acetone, C₂-C₁₅alcohols, chloroform, dioxane, chlorobenzene, benzene, toluene, xylene,sulfolane, pyridine, quinoline, 2,4,6-trimethylpyridine, acetamide,di-(C₁-C₂)alkylacetamide, and 1-methyl-2-pyrrolidinone (NMP).

When Z is NH, an excess of R⁵ZH, may be used both as the reagent and asthe base. Examples of bases other than R⁵ZH that may be used includepotassium carbonate, sodium hydride, potassium hydride, sodium (C₁-C₄)alkoxides, potassium (C₁-C₄) alkoxides, sodium, sodium amide,tri-[(C₁-C₄) alkyllamines, organolithium or organosodium compounds suchas n-butyllithium, s-butyllithium, t-butyllithium, lithiumdiisopropylimide, lithium bis(trimethylsilyl)amide, sodiumdiisopropylamide or sodium bis(trimethylsilyl)amide, and organometallicbases such as Grignard reagents. This reaction is generally carried outin an appropriate solvent (e.g., THF, dioxane, sulfolane, DMSO, toluene,DMF or NMP, with or without an additional catalyst such as a copperhalide, oxide or sulfate e.g., Cul, CuBr, Cu₂O, CuCl, CuSO₄ Cu₂. CuBr₂,CuCl₂ or Cu(O)), a Pd(O) salt such as Pd(PPH₃)₄, a Pd(II) salt such asPd(OAc)₂ (wherein OAc is acetate) with racemic or (R)— or(S)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP), at temperaturefrom about room temperature to about 270° C.

When Z is oxygen or sulfur, a base that is capable of deprotonating R⁵ZHmay be used, such as potassium carbonate, sodium carbonate, sodium,sodium amide, an alkali metal hydride such as sodium or potassiumhydride, a sodium (C₁-C₄ alkoxide), a potassium (C₁-C₄ alkoxide), sodiumamide, a tri-[(C₁-C₆)alkyl]amide or an organometallic base such asn-butyllithium, s-butyllithium, t-butyllithium, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, sodiumdiisopropylamide or sodium bis(trimethylsilyl)amide. The reactiontemperature can range from about 0° C. to about 180° C. and ispreferably from about 50° C. to about 140° C. Suitable solvents includeDMSO, THF, sulfolane, dioxane and NMP.

When Z is CHCN or CHCOO(C₁-C₄ alkyl), a base that is capable ofdeprotonating R⁵ZH may be used, such as an alkali metal hydride (e.g.,sodium or potassium hydride), a sodium (C₁-C₄ alkoxide) or anorganometallic base such as n-butyllithium, s-butyllithium,t-butyllithium, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, sodium diisopropylamide or sodiumbis(trimethylsilyl)amide, in an appropriate solvent, e.g., THF, DMSO,dioxane, methylene chloride, chloroform, toluene, xylene, benzene or aC₁-C₆ alkanol.

When Z is CR¹³CN, compounds of formula I may be prepared by reacting thecorresponding compounds wherein Z is CHCN first with a base such as analkali metal hydride such as sodium or potassium hydride,n-butyllithium, s-butyllithium, t-butyllithium, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide or sodiumdiisopropylamide, and then with a compound of the formula R¹³L wherein Lis a leaving group such as iodo, chloro, bromo, mesylate (OMs) ortosylate (OTs).

Compounds of the formula I wherein Z is CHR¹³ may be prepared by acidhydrolysis (using, e.g., 85% phosphoric acid) of the correspondingcompounds wherein Z is CR¹³CN, followed by decarboxylation upon heatingin an oil bath at a temperature from. about 120° C. to about 180° C.Further alkylation in the presence of base and a compound of the formulaand R¹⁴L, wherein L is defined as above, will provide the correspondingcompounds of formula I wherein Z is CR¹³R¹⁴.

When Z is N(C₁-C₄ alkyl), compounds of the formula I may be prepared byreacting the corresponding compounds wherein Z is NH first with a baseand then with a compound of the formula (C₁-C₄ alkyl)-L, wherein L isdefined as above. Bases such as lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, sodium diisopropylamide may be used. Suitablesolvents include THF, methylene chloride (CH₂Cl₂), DMSO, DMP, NMP anddioxane. The reaction temperature may range from about 20° C. to about150° C., and is preferably from about room temperature to about 100° C.

Compounds of formula I wherein D is carbon and B is —NR¹R², —OCHR¹R² or—SCHR¹R² may be prepared by reacting the corresponding compounds offormula III, wherein U is chloro, bromo or iodo, with a compound of theformula BH in the presence of a base, using methods analogous to thosedescribed above for the conversion of compounds of the formula II intocompounds of the formula I.

Compounds of formula I wherein D is carbon and B is —CR¹R²R¹⁰,—C(═CR²R¹¹)R¹, —CR²R¹⁰NHR¹, —CR²R¹⁰OR¹, —CR²R¹⁰SR¹ or —COR² may beprepared by reacting the corresponding compounds of formula III, whereinU is cyano, with a Grignard reagent containing the desired R² group toform a compound of the formula I wherein B is COR². Further reaction ofthis compound with a Grignard reagent containing the desired R¹ groupwill yield the compound of formula I wherein B is —CR¹ R²(OH).

Compounds of the formula I wherein B is —CR¹R²R¹¹, or —C(C═CR²R¹¹)R¹ maybe prepared using conventional methods well known to those skilled inthe art. For example, reaction of compounds of the formula I wherein Bis —C(OH)R¹ R² with an acid such as concentrated sulfuric acid in aceticacid, or a Burgess inner salt (such as(carboxysulfamoyl)triethylammonium hydroxide methyl ester) will yield acompound of the formula I wherein B is —C(═CR²R¹¹)R¹. Hydrogenation of acompound of the formula I wherein B is —C(═CR²R¹¹)R¹ using a Pd/C(palladium on carbon) or platinum oxide catalyst, using standard methodswell known in the art, will yield a compound of formula I wherein B is—CHR¹R². Reaction of compounds in formula I wherein B is —CR¹R²(OH) withdiethylaminosulfur trifluoride or triphenylphosphine/carbontetrachloride will afford a compound of formula I wherein B is —CR¹R²For —CR¹R²Cl, respectively.

Reduction of compounds of the formula I wherein B is —COR² with sodiumborohydride in a reaction inert solvent such as a (C₁-C₄ alcohol), THFor dioxane, preferably methanol, at a temperature from about roomtemperature to about 100° C, preferably from about room temperature toabout 60° C., will yield a compound of the formula I wherein B is—CHR²OH. Alkylation of the —CHR²OH group with an alkyl halide (such asan alkyl iodide) in the presence of a base (such as sodium hydride,potassium hydride or sodium or lithium bis(trimethylsilyl)amide) atabout room temperature will afford the corresponding compound of formulaI wherein B is —CHR²OR¹. Compounds of formula I wherein B is —CR²R¹⁰NHR¹may also be prepared by a conventional methods well known in the art,such as reductive amination of the corresponding compounds of formula Iwherein B is —COR² with an appropriate amine and reducing agent (e.g.,sodium cyanoborohydride or sodium triacetoxylborohydride) in anappropriate solvent (e.g., a lower alkanol or acetic acid).

Compounds of the formula ill wherein U is CN may be prepared by reactingthe corresponding compounds of the formula lIl wherein U is chloro,bromo, iodo, or —OCOCF₃ with potassium cyanide or copper cyanide indimethylsulfoxide, THF, methylene chloride, toluene or DMF, with orwithout a Pd(0) or Pd(II) catalyst, at a temperature from about roomtemperature to about 180° C., preferably at about the refluxtemperature.

Compounds of the formula Ill wherein U is chloro, bromo, iodo, or—OCOCF₃ may be prepared from the corresponding compounds of the formulaIII wherein U is hydroxy or amino. Compounds of the formula III whereinU is halo, or —OCOCF₃ may be prepared by reacting a compound of theformula III wherein U is amino with a compound of the formula (C₁-C₅alkyl)-O-N═O and a copper (II) halide in an appropriate solvent such asacetonitrile, acetone, toluene, methylene chloride or dichloroethane, ata temperature from about room temperature to about the refluxtemperature. This reaction is preferably carried out in acetonitrile atthe reflux temperature.

Compounds of formula III wherein U is chloro or bromo may be prepared byreacting the corresponding compounds of the formula III wherein U ishydroxy with a compound of the formula POX₃, wherein X is chloro orbromo, with or without di-(C₁-C₄alkyl)aniline. This reaction may beconducted neat or in a solvent such as dimethylformamide, dichloroethaneor methylene chloride, at a temperature from about 100° C. to about 180°C. Compounds of formula III wherein U is —OTf (wherein Tf is triflate)may be prepared by reacting the corresponding compounds of the formulaIII wherein U is OH with Tf₂O in the presence of a base such astri-(C₁-C₄ alkyl) amine or pyridine or an appropriate pyridinederivative (e.g., dimethylaminopyridine) in an appropriate solvent suchas methylene chloride, DMF, DMSO, chloroform, or THF. Reaction ofcompounds of formula III wherein U is OTf with a compound of the formulaKX, NaX or CuX (wherein X is chloro, bromo or iodo) in an appropriatesolvent such as DMF, dimethylacetamide, N-methyl-pyrrolidone (NMP), orDMSO at temperature between about room temperature and about 180° C.will yield compounds of the formula III wherein U is chloro, bromo oriodo.

Compounds of formula I, II, and III, wherein Z and R⁵ are defined asabove for formula I and R³ is —O-(C₁-C₄) alkyl or —S-(C₁-C₄) alkyl(hereinafter R²⁰) may be prepared by reacting the correspondingcompounds of the formula I, wherein R³ is chloro, bromo, OTs or iodo,with a nucleophile of the formula R²⁰H, wherein R²⁰H is a (C₁-C₆)alkanolor a (C₁-C₆)alkane thiol, optionally in the presence of an organic orinorganic base. Suitable bases include sodium, sodium hydride, potassiumhydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide andsodium diisopropylamide. Compounds of the formula I wherein R³ is fluoromay be prepared by reacting the corresponding compounds wherein R³ ischloro, bromo, iodo, —OCOCF₃, or —OSO₂CF₃ with tetrabutylammoniumfluoride, potassium fluoride or another suitable fluoride agent, usingstandard methods well known to those skilled in the art.

Compounds of formula I wherein G is O, S, or NR⁸ may be prepared fromcompounds of formula IV-a, as illustrated in Scheme 1. Referring toScheme 1, compounds of the formula IV-b may be prepared by reacting theappropriate compound of the formula IV-a, wherein B is —CR¹R²R¹⁰,—C(═CR²R¹¹)R¹, CR¹R¹⁰OR¹, CR²R¹⁰SR¹ or COR2; Y is O, S, NR⁸; and A isCR⁷ or N, with an acyl halide such as L-(CH₂)_(n)—COX (wherein X ischloro, bromo, iodo, mesylate, tosylate, triflate or OCOCF₃; and L ischloro, bromo, iodo, hydroxy, mesylate, tosylate, triflate or OCOCF₃),or an anhydride (such as [C₁-C₄alkyl)CO]₂O) in the presence of a basesuch as a tri-(C₁-C₄ alkyl)amine, pyridine or a substituted pyridine, inan appropriate solvent such as methylene chloride, chloroform, THF,DMSO, dioxane, ether, dimethoxyethane, at a temperature from about 0° C.to about 180° C., preferably from about room temperature and about 60°C.

Compounds of formula la may be prepared by reacting the correspondingcompounds of the formula IV-b with a base. Suitable bases for use inthis reaction include sodium, sodium hydride, potassium hydride, lithiumdiisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide,sodium diisopropylamide or sodium or potassium carbonate. Alkylation ofthe resulting compounds of the formula Ia with a base, followed byquenching with alkyl halide in an appropriate solvent such as ether,THF, methylene chloride, dioxane, benzene, toluene, or dimethoxyethane(DME), with or without hexamethylphosphoramide (HMPA), at temperaturefrom about −78° C. to about room temperature, will afford thecorresponding compounds of the formula Ic. Suitable bases for use inthis reaction include lithium diisopropyilnide, lithiumbis(trimethylsilyl)amide, sodium diisopropylamide, and butyl lithium.Reduction of compounds of the formula I-a or I-c with a reducing agentsuch as borane methyl sulfide complex (BH₃•DMS), borane (BH₃), boraneTHF complex (BH₃•DMS), diisobutylaluminum hydride or lithium aluminumhydride will yield the corresponding compounds of the formula I-b orI-d, respectively.

Compounds of formula I wherein G is carbon may be prepared fromcompounds of formula IV-c, as illustrated in Scheme 2. Referring toscheme 2, compounds of formula 1-e may be prepared by cyclization ofcompounds of formula IV-c wherein Q is (C₁-C₂ alkyl)CR⁴(COOC₁-C₄alkyl)₂, (C₁-C₂ alkyl)CR⁴(COOC₁-C₄ alky), (C₁-C₂ alkyl)CR₄(CN)₂, (C₁-C₂alkyl)CR⁴(CN) or (C₁-C₂ alkyl)CR⁴COOH using standard methods for amideformation that are well known in the literature. Such methods includeacid cyclization (such as: (a) heating in 40-85% phosphoric acid at atemperature from about 100° C. to about 150° C.; (b) heating in aqueousacetic acid/hydrochloric acid; or (c) base hydrolysis; followed bydecarboxylation and then amide cyclization). Compounds of formula I-fmay be obtained by reduction of the corresponding compounds of theformula I-e using the methods analogous to those described above forconversion of compounds of the formula I-a into those of the formulaI-b.

Compounds of formula IV-c wherein Q is (C₁-C₂ alkyl)CR⁴(COOC₁-C₄ alkyl)₂or (C₁-C₂ alkyl)CR⁴(CN)₂ can be prepared by reaction of a compound ofthe formula Na—, K— or Li—CR⁴(COOC¹—C⁴ alkyl)₂ or Na—, K— or Li—CR⁴(CN)₂with a compound in formula IV-c wherein Q is CHR⁸X or CHR⁸CHR⁴X (whereinX is chloro, bromo or iodo), at a temperature between about 0° C. andabout 150° C., preferably between about 10° C. to about 60° C., in anappropriate solvent such as THF, DMSO, DMF, a (C₁-C₅ alkyl)-alcohol,acetonitrile, acetone, toluene, NMP or dimethyl acetamide. The preferredsolvent is DMSO. Other compounds of formula IV may be prepared bymethods analogous to those described in World Patent Application WO95/33750, which designates the United States and which was published onMay 18, 1995. This application is incorporated herein by reference inits entirety.

Compounds of formula I wherein E is CR⁶, G is CR⁸, D is nitrogen and Kis oxygen may be prepared by reacting compounds of the formula IV-cwherein Q is CHR⁸OH with aqueous formaldehyde or R⁶CHO in an appropriatesolvent such as benzene, toluene, xylene, a C₁-C₅ alkyl alcohol oracetonitrile, in the presence of acid catalyst such as p-TsOH, H₂SO₄ orHCl, at a temperature from about room temperature to about 160° C.,preferably at about the reflux temperature. Toluene or benzene ispreferred solvent.

Compounds of formula IV-c may be prepared by the methods described inWorld Patent Application WO 95/33750, which designates the United Statesand was published on May 18,1995.

The acid addition salts of compounds of the formula can be prepared in aconventional manner by treating a solution or suspension of thecorresponding free base with one chemical equivalent of apharmaceutically acceptable acid. Conventional concentration orcrystallization techniques can be employed to isolate the salts.Illustrative of suitable acids are acetic, lactic, succinic, maleic,tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric,sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic,sulfonic acids such as methanesulfonic, benzene sulfonic,p-toluenesulfonic, and related acids.

The compounds of formula I and their pharmaceutically acceptable salts(hereinafter referred to, collectively, as “the active compounds of thisinvention”) may be administered alone or in combination withpharmaceutically acceptable carriers, in either single or multipledoses. Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solutions and various organic solvents Thepharmaceutical compositions formed by combining the novel compounds offormula I and pharmaceutically acceptable carriers can then be readilyadministered in a variety of dosage forms such as tablets, powders,lozenges, syrups, injectable solutions and the like. Thesepharmaceutical compositions can, if desired, contain additionalingredients such as flavorings, binders, excipients and the like. Thus,for purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch, methylcellulose, alginic acid and certain complex silicates,together with binding agents such as polyvinylpyrrolidone, sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in soft and hard filled gelatin capsules. Preferred materialsfor this include lactose or milk sugar and high molecular weightpolyethylene glycols. When aqueous suspensions or elixirs are desiredfor oral administration, the essential active ingredient therein may becombined with various sweetening or flavoring agents, coloring matter ordyes and, if desired, emulsifying or suspending agents, together withdiluents such as water, ethanol, propylene glycol, glycerin andcombinations thereof.

For parenteral administration, solutions containing an active compoundof this invention or a pharmaceutically acceptable salt thereof insesame or peanut oil, aqueous propylene glycol, or in sterile aqueoussolution may be employed. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular aqueous solutionsare especially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

The effective dosages for the active compounds of this invention willdepend on the intended route of administration and factors such as theage and weight of the patient, as generally known to a physician. Thedosages will also depend on the particular illness to be treated. Forinstance, the daily dosage for stress-induced illnesses, inflammatorydisorders, Alzheimer's disease, gastrointestinal diseases, anorexianervosa, hemorrhagic stress and drug and alcohol withdrawal symptomswill generally range from about 0.1 to about 50 mg/kg body weight of thepatient to be treated.

Methods that may be used to determine the CRF antagonist activity of theactive compounds of this invention and their pharmaceutically acceptablesalts are described in Endocrinology, 116, 1653-1659 (1985) andPeptides, 10, 179-188 (1985). The binding activities for compounds ofthe formula I, expressed as IC₅₀ values, generally range from about 0.5nanomolar to about 10 micromolar. Methods that can be used to determinethe CRF binding protein inhibiting activity of compounds of the formulaI can be determined using the method described in Brain Research,(1997), 745 (1,2), 248-255.

The present invention is illustrated by the following examples. It willbe understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (¹H NMR) and C¹³ nuclearmagnetic resonance spectra (C¹³ NMR) were measured for solutions indeuterochloroform (CDCl₃) and peak positions are expressed in parts permillion (ppm) downfield from tetramethylsilane (TMS). The peak shapesare denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet;m, multiplet; b, broad.

The following abbreviations are used in the Examples: Ph=phenyl;iPr=isopropyl; HRMS=high resolution mass spectrum.

EXAMPLE 11-(1-Ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one

To a solution of2-chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamide(170 mg, 0.42 mml) in 2 ml of dry THF was added a solution of 1 Mlithium bis(trimethylsilyl)amide in THF (0.84 ml, 0.84 mmol) at −78° C.The mixture was gradually warmed to room temperature and stirred at roomtemperature for 2 hours. An additional 0.42 ml of 1M lithiumbis(trimethylsilyl)amide in HF was added at −78° C. and the resultingmixture was stirred at room temperature overnight. The mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas dried and concentrated to dryness to give 160 mg of yellow solid.The solid residue was purified through silica gel column chromatographyusing 15% ethyl acetate (EtOAc) in hexane as eluent to give 91 mg (59%)of the title compound as white crystals. ¹H NMR (CDCl₃) δ 7.84 (s, 1H),6.88 (s,2H), 6.22 (s,1H), 3.82(s,2H), 3.58(m,1H), 2.30(s,3H),2.18(s,3H), 2.08(s,6H), 1.63(m,4H), 0.95(m,6H) ppm.

EXAMPLE 21-(1-Ethyl-Propyl)4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy-1,4-Dihydro-2H-pyrido[3,4-b]pyrazin-3-one

To a solution of1-(1-Ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one(50 mg, 0.136 mmol) in 2 ml of dry THF was added IM lithiumbis(trimethylsilyl)amide in THF (0.14 ml) at −78° C. and the mixture wasstirred at that temperature for 20 min. An excess of methyl iodide wasadded at −78° C. and the resulting mixture was stirred at thattemperature for 20 min, then gradually warmed to room temperature andstirred for an additional 2 hours. The mixture was quenched with waterand extracted with ethyl acetate. The organic layer was dried andconcentrated to give 61 mg of pale yellow solid. The solid was purifiedthrough silica gel column chromatography using 10% ethyl acetate inhexane as eluent to give 28 mg of the title compound as white crystals,mp 112-114° C.; ¹H NMR (CDCl₃) δ 6.89(s,2H), 6.29(s,1H), 3.63(s,2H),3.59(s,3H), 3.48(m,1H), 2.31(s,3H), 2.18(s,3H), 2.10(s,6H), 1.60(m,4H),0.94(t,6H) ppm.

EXAMPLE 31-(1-Ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine

A mixture of1-(1-Ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one(21 mg, 0.055 mmol) and 2 M borane dimethylsulfide complex (BH₃•DMS)(0.07 ml, 0.14 mmol) in 2 ml of dry THF was heated at reflux for 3hours. The mixture was cooled to 0° C. and quenched with 0.2 ml of meohand 0.2 ml of concentrated hydrochloric acid (HCl). The resultingmixture was stirred at room temperature for 2 hours and concentrated todryness. The residue was quenched with water and extracted withchloroform. The organic layer was dried and concentrated to give 19 mgof a clear oil that was purified through silica gel columnchromatography using 10% ethyl acetate in hexane as eluent to give 11 mgof the title compound as white crystals, mp 78-80° C.; ¹H NMR (CDCl₃) δ6.85(s,2H), 6.28(s,1H), 3.73(m,1H), 3.12 (m,4H), 2.85(s,3H), 2.29(s,3H),2.,13(s,3H), 2.11 (s,6H), 1.61(m,4H), 0.90(t,6H) ppm.

EXAMPLE 41-(1-Ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine

The title compound was prepared as a tan crystals, mp 138-140° C., bythe procedure analogous to that in Example 3 starting from1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4b]pyrazin-3-one.¹H NMR (CDCl₃) δ 6.87(s,2H), 6.17(s,1H), 3.62(m,1H), 3.39(m,2H),3.32(m,2H), 2.29(s,3H), 2.13(s,3H), 2.11(s,6H), 1.59(m,4H), 0.91(t,6H)ppm.

EXAMPLE 51-(1-Ethyl-propyl)7-methyl2-oxo5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylicAcid Methyl Ester

A mixture of2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonicacid dimethyl ester (22 mg, 0.048 mmol) and 2 ml of acetic acid andbubbled through HCl (g) was heated at 130° C. for 30 hours. The reactionwas cooled and concentrated to dryness. The residue was quenched withwater and extracted with ethyl acetate. The organic layer was dried andconcentrated to give 7 mg of the title compound. ¹H NMR (CDCl₃) δ6.89(s,2H), 6.59(s,1H), 4.4(m,1H), 3.72(s,3H), 3.6-3.8(m,1H),3.4-3.6(m,1H), 3.1-3.2(dd,1 H), 2.31(s,3H), 2.28(s,3H), 2.06(s,6H),1.8-2.2(m,4H), 0.92(t,6H) ppm.

EXAMPLE 61-(1-Ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine3-carboxylicAcid Isopropyl Ester

The title compound was prepared by the method analogous to that inExample 5 starting from2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonicacid diisopropyl ester. ¹H NMR (CDCl₃) δ 6.88(s,2H), 6.57(s,1H),5.00(m,1H), 3.4-3.6(m,2H), 3.15(dd,1H), 2.30(s,3H), 2.24(s,3H),2.05(s,6H), 2.0-2.3(m,3H), 1.75-1.95(m,2H), 1.22(d,3H), 1.14(d,3H),0.93(t,6H) ppm.

EXAMPLE 71-(1-Ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A mixture of2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonicacid diisopropyl ester (40 mg, 0.078 mmol) and 85% phosphoric acid washeated at 73° C. overnight, and then heated at 133° C. for 1 hour. Thereaction mixture was cooled, quenched with water and extracted withethyl acetate. The organic layer was washed with brine, dried andconcentrated to give a brown oil. The oil residue was purified throughsilica gel column chromatography using 3% ethyl acetate in hexane aseluent to give 28 mg (98%) of the title compound. ¹H NMR (CDCl₃) δ6.89(s,2H), 6.56(s,1H), 4.4(m,1H), 3.00(m,2H), 2.67(m,2H), 2.31(s,3H),2.25(s,3H), 2.07(s,6H), 1.86(m,4H), 0.90(t,6H) ppm.

EXAMPLE 81-(1-Ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine

The title compound was prepared as a white solid, by the procedureanalogous to that of EXAMPLE 3 starting from1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one.¹H NMR (CDC₁ ₃) δ 6.83(s,2H), 6.14(s,1H), 3.63(m,1H), 3.08(m,2H),2.75(m,2H), 2.26(s,3H), 2.10(s,3H), 2.07(s,6H), 1.90(m,2H), 1.54(m,4H),0.87(t,6H) ppm.

EXAMPLE 91-(1-Ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene

A mixture of1-(1-ethyl-propylamino)-6methyl-2-(2,4,6tnimethyl-phenoxy)-pyridin-3-yl]-methanol(42 mg, 0.122 mmol) and 37% formaldehyde (0.05 ml) andpara-toluene-sulfonic acid (p-TsOH) (35 mg) in 3.5 ml of toluene washeated at reflux under a Dean-Stark trap for 15 hours. The mixture wasquenched with water, saturated sodium bicarbonate and extracted withethyl acetate. The oraganic layer was dried and concentrated to give 52mg of crude product as light green solid. The crude material waspurified through silica gel column chromatography using 1:1 hexane/CHCl₃as eluent to give 34 mg (86%) of the title compound as white crystals,mp 112-114° C. ¹H NMR (CDCl₃) δ 6.86(s,2H), 6.25(s,1H), 4.92(s,2H),4.68(s,2H), 3.54(m,1H), 2.29(s,3H), 2.17(s,3H), 2.07(s,6H),1.5-1.7(m,4H), 0.95(t,6H) ppm.

EXAMPLE 101-(1-Ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene

The title compound was prepared as a white solid by the method analogousto that described in EXAMPLE 9 starting from1-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-ethanol.¹H NMR (CDCl₃) δ 6.87(s,2H), 6.26(s,1H), 5.16(q,1H), 4.7(Abq, 2H),3.63(m,1H), 2.29(s,3H), 2.15(s,3H), 2.08(s,6H), 1.65(d,3H),1.5-1.8(m,4H), 0.96(m,6H)ppm.

EXAMPLE 111-(1-Ethyl-propyl)-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-[1,6]-naphthyridin-2-one

A mixture of2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]methyl]-2-methyl-malonicacid dimethyl ester (130 mg) and 85% phosphoric acid (4 ml) and water (4ml) was heated at reflux for 16 hours. The mixture was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith water and saturated sodium bicarbonate and brine, dried andconcentrated to give 80 mg of clear oil. The oil was purified throughsilica gel column chromatography using hexane to 10% ethyl acetate inhexane as eluent to give 67 mg (64%) of the title compound as a whitesolid. ¹H NMR (CDCl₃) δ 6.87(s,2H), 6.53(s,1H), 4.3(m,1H), 3.14(m,1H),2.69(m,2H), 2.29(s,3H), 2.22(s,3H), 2.05(s,6H), 1.83(m,4H), 1.25(d,3H),0.86(t,6H) ppm.

EXAMPLE 121-(1-Ethyl-propyl)-3,3,6-trimethyl-4-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

A solution of1-(1-ethyl-propyl)-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6]-naphthyridin-2-one(56 mg) in 4 ml of dry THF was treated with a 2.0 M borane-dimethylsulfide complex in THF (0.3 ml) and heated at reflux for 1 hour. Themixture was quenched with water and extracted with ethyl acetate. Theorganic layer was dried and concentrated to give 50 mg of the titlecompound as colorless oil. The oil was purified through silica gelcolumn chromatography using 10% ethyl acetate in hexane as eluent toyield 22 mg of the titole compound as white solid, ¹H NMR (CDCl₃) d6.83(s,2H), 6.15(s,1H), 3.65(m,1H), 3.12(m,1H), 2.98(m,1H), 2.62(m,1H),2.26(s,3H), 2.23(m,1H), 2.12(s,3H), 2.06(s,6H), 1.95(m,1H), 1.57(m,4H),1.07(d,3H), 0.87(t,6H) ppm.

EXAMPLE 13[1-(1-Ethyl-propyl)-7-methyl-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine

A mixture of[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol(280mg, 0.82 mmol), 37% aqueous formaldehyde(0.35 ml) and p-TsOH (78 mg,0.41 mmol) in 10 ml of toluene was heated at reflux using a Dean-Starkapparatus for 3 hours. The mixture was quenched with water and extractedwith ethyl acetate. The organic layer was separated, dried andconcentrated to give 280 mg of a green oil. The oil was purified throughsilica gel column chromatography using EtOAc as eluent to give the titlecompound as a brown oil. ¹H NMR (CDCl₃) δ 6.89 (s,2H), 6.09(s,IH),4.51(s,2H), 4.19(s,2H), 3.53(m,1H), 2.25(s,6H), 2.15(s,6H), 1.55(m,4H),0.90(t,6H)ppm.

EXAMPLE 141-(1-Ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenylamino)-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A mixture of2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonicacid dimethyl ester (100 mg, 0.219 mmol), 85% phosphoric acid (3 ml) andwater (3 ml) was heated at reflux for 2 hours. The reaction mixture wascooled to rt, diluted with water and neutralized to pH 6 with diluteNaOH and extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous MgSO₄, filtered, and concentrated to drynessto give 61 mg of a yellow foam. The oil was purified through silca gelcolumn chromatography using 10% EtOAc in hexane as eluent to give 41 mgof the title compound as a tan solid, mp 44-46° C. ¹H NMR (CDC₁ ₃) δ6.87(s,2H), 6.36(s,1H), 5.64(brs,1H), 4.21(m,1H), 2.51(m,2H),2.37(m,2H), 2.29(s,3H), 2.27(s,3H), 2.11(s,6H), 2.02(m,2H), 1.76(m,2H),0.86(t,6H) ppm.

EXAMPLE 151-(1-Ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4dihydro-1H-pyrido[4,3-d]pyrimidin-2-one

To a mixture of[3-Aminomethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine(100 mg, 0.292 mmol) in dry THF was added triphosgene (34 mg, 0.114mmol) at 0° C. The reaction mixture was allowed to gradually warm to rtand stir for 2 h. The mixture was quenched with water and extracted withethyl acetate. The organic layer was dried and concentrated to drynessto give 130 mg of a clear oil. The solid was purified through silica gelcolumn chromatography using 10% EtOAc in hexane as eluent to give 89 mg(82.4%)of the title compound as a white crystalline solid, mp 197-199°C. ¹H NMR (CDCl₃) d 6.86(s,2H), 6.44(s,1H), 5.14(brs,1H), 4.49(s,2H),4.20(m,1H), 2.28(s,3H), 2.22(s,3H), 2.04(s,6H), 1.67(m,4H),0.94(t,6H)ppm.

PREPARATION A2-Chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamide

A mixture of2-(2,4,6-trimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,4-diamine(250 mg, 0.76 mmol) and triethylamine (0.11 ml, 0.76 mmol) in 5 ml ofdry THF was treated with chloroacetyl chloride (0.06 ml, 0.76 mmol) at0° C. The resulting mixture was stirred at room temperature for 1 hour.The mixture was quenched with water and extracted with ethyl acetate.The organic layer was dried and concentrated to give 310 mg of greencrystals that was purified through silica gel column chromatographyusing 10% ethyl acetate in hexane as eluent to give 280 mg (90%) of thetitle compound as tan crystals, mp 152-154° C. ¹H NMR (CDCl₃) δ8.07(s,1H), 6.88(s,2H), 6.16(s,1H), 4.75(brs,1H), 4.25(s,2H),3.33(m,1H), 2.30(s,3H), 2.18(s,3H), 2.08(s,6H), 1,4-1.8(m,4H),0.97(t,6H) ppm.

PREPARATION B2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]methyl-2-methyl-malonicAcid Dimethyl Ester

A mixture of methyl dimethylmalonate (260 mg) and 60% sodium hydride inoil (70 mg) in 4 ml of DMSO was stirred at room temperature for 10 min.A solution of3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine(200 mg) in 2 ml of DMSO was added. The mixture was stirred at roomtemperature for 3 hours. The mixture was quenched with water andextracted with ethyl acetate. The organic layer was dried andconcentrated to give the crude material which was purified throughsilica gel using hexane to 10% ethyl acetate in hexane as eluent to give137 mg of2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]methyl]-2-methyl-malonicacid dimethyl ester as a white solid. ¹H NMR (CDCl₃) δ 6.83(s,2H),6.01(s,1H), 5.00(m,1H), 3.70(s,6H), 3.40(s,2H), 3.25(m,1H), 2.27(s,3H),2.12(s,3H), 2.05(s,6H), 1.5-1.7(m,4H), 1.48(s,3H), 0.94(t,6H)ppm.

What is claimed is:
 1. A compound of the formula

the dashed lines represent optional double bonds; A is CR⁷; B is —NR¹R²,—CR¹R²R¹⁰, —C(═CR²R¹¹)R¹, —NHCR¹R²R¹⁰, —OCR¹R²R¹⁰, —SCR¹R²R¹⁰,—CR²R¹⁰NHR¹, —CR²R¹⁰OR¹, —CR²R¹⁰SR¹ or —COR², and is single bonded to D;or B is —CR¹R², and is double bonded to D and D is carbon; D is nitrogenor CR⁴ and is single bonded to all atoms to which it is attached, or Dis carbon and is double bonded to E or double bonded to B; E isnitrogen, C═O, C═S, CR⁶R¹², NR⁶ or CR⁶; K and G are each, independently,C═O, C═S, CHR⁸ or NR⁸ when single bonded to both adjacent ring atoms, ornitrogen or CR⁸ when it is double bonded to an adjacent ring atom; the6-membered ring that contains D, E, K and G may contain from one tothree double bonds; with the proviso that one of D, E, K, and Gcomprises a nitrogen atom that is a member of the 6-membered ringcontaining D,E, K and G, and the remaining of D, E, K, and G comprisecarbon atoms that are each members of said 6-membered ring; R¹ is C₁-C₆alkyl optionally substituted with from one or two substituentsindependently selected from hydroxy, fluoro, chloro, bromo, iodo, C₁-C₄alkoxy, CF₃, —C(═O)(C—C₄alkyl), —C(═O)—O—(C₁-C₄)alkyl, —OC(═O)(C₁-C₄alkyl), —OC(═O)N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —NHCO(C₁-C₄ alkyl), —COOH,—COO(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl),—S(C₁-C₄ alkyl), —CN, —NO₂, —SO(C₁-C₄ alkyl), —SO₂(C₁-C₄ alkyl),—SO₂NH(C₁-C₄ alkyl) and —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), wherein each ofthe C₁-C₄ alkyl groups in the foregoing R¹ groups may optionally containone or two double or triple bonds; R² is C₁-C₁₂ alkyl which mayoptionally contain from one to three double or triple bonds, aryl or(C₁-C₄ alkylene)aryl, wherein said aryl and the aryl moiety of said(C₁-C₄ alkylene)aryl is selected from phenyl, naphthyl, thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl,furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, pyrazolyl,pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl and benzoxazolyl; C₃-C₈cycloalkyl or (C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), wherein one or two ofthe carbon atoms of said cycloalkyl and the 5 to 8 membered cycloalkylmoieties of said (C₁-C₆ alkylene)(C₃-C₈ cycloalkyl may optionally andindependently be replaced by an oxygen or sulfur and wherein each of theforegoing R² groups may optionally be substituted with from one to threesubstituents independently selected from chloro, fluoro, hydroxy andC₁-C₄ alkyl, or with one substituent selected from C₁-C₆ alkoxy,—OC(═O)(C₁-C₆ alkyl), —OC(═O)N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —S(C₁-C₆alkyl), amino, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)—CO—(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl), —COOH, —COO(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SH, —CN, —NO₂,—SO(C₁-C₄ alkyl), —SO₂(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkyl) and —SO₂N(C₁-C₄alkyl)(C₁-C₂ alkyl); —NR¹R² or CR¹R²R¹⁰ may form a ring selected fromsaturated 3 to 8 membered rings, the 5 to 8 membered rings of which mayoptionally contain one or two double bonds, and wherein one or two ofthe ring carbon atoms of such 5 to 8 membered rings may optionally andindependently be replaced by an oxygen or sulfur atom or by NZ³ whereinZ³ is hydrogen or C₁-C₄ alkyl; R³ is hydrogen, C₁-C₄ alkyl, —O(C₁-C₄alkyl), chloro, fluoro, bromo, iodo, —S(C₁-C₄ alkyl) or —SO₂(C₁-C₄alkyl); R⁴ is hydrogen, C₁-C₂ alkyl, hydroxy or fluoro; each R⁶, R⁸ andR⁹ that is attached to a carbon atom is selected, independently, fromhydrogen, C₁-C₂ alkyl, fluoro, chloro, bromo, iodo, hydroxy,hydroxymethyl, formyl, trifluoromethyl, cyano, amino, nitro, —O(C₁-C₂alkyl), —N(C₁-C₂ alkyl)(C₁-C₂ alkyl), —S(C₁-C₂ alkyl), —CO(C₁-C₂ alkyl),—C(═O)H or —C(═O)O(C₁-C₂ alkyl), wherein each of the C₁-C₂ alkylmoieties in the foregoing R⁶, R⁸, and R⁹ groups may optionally containone double or triple bond; and each R⁶, R⁸, and R⁹ that is attached to anitrogen atom is selected, independently, from hydrogen and C₁-C₄ alkyl;R⁵ is substituted phenyl, naphthyl, pyridyl or pyrimidyl, wherein eachof the foregoing R⁵ groups is substituted with from two to foursubstituents R¹⁵, wherein from one to three of said substituents may beselected, independently, from chloro, C₁-C₆ alkyl, —O(C₁-C₆ alkyl) and—(C₁-C₆alkylene)O(C₁-C₆alkyl), and wherein one of said substituents maybe selected, independently, from bromo, iodo, formyl, cyano,trifluoromethyl, nitro, amino, —NH(C₁-C₄ alkyl), —N(C₁-C₂ alkyl)(C₁-C₆alkyl), —C(═O)O(C₁-C₄ alkyl), —C(═O)(C₁-C₄ alkyl), —COOH, —SO₂NH(C₁-C₄alkyl), —SO₂N(C₁-C₂ alkyl)(C₁-C₄ alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl),—S(C₁-C₆ alkyl) and —SO₂(C₁-C₆ alkyl), and wherein each of the C₁-C₄alkyl and C₁-C₆ alkyl moieties in the foregoing R⁵ groups may optionallybe substituted with one or two substituents independently selected fromfluoro, hydroxy, amino, methylamino, dimethylamino and acetyl; R⁷ ishydrogen, methyl, halo (e.g., chloro, fluoro, iodo or bromo), hydroxy,methoxy, —C(═O)(C₁-C₂ alkyl), —C(═O)O(C₁-C₂ alkyl), trifluoromethoxy,hydroxymethyl, trifluoromethyl or formyl; R¹⁰ is hydrogen, hydroxy,methoxy or fluoro; R¹¹ is hydrogen or C₁-C₄ alkyl; R¹² is, hydrogen ormethyl; and Z is NH, oxygen, sulfur, —N(C₁-C₄ alkyl), or CR¹³R¹⁴ whereinR¹³ and R¹⁴ are independently selected from hydrogen, and methyl withthe exception that one of R¹³ and R¹⁴ may optionally be cyano; with thefurther proviso that: (a) in the six or seven membered rings ofstructures in formula I, there can not be two double bonds adjacent toeach other; and (b) when D is carbon and is double bonded to B, then Bis CR¹R²; or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1 wherein B is —CHR¹R² or —NR¹R², and R¹ is C₁-C₆alkyl which may optionally be substituted with one hydroxy, fluoro,trifluoromethyl or C₁-C₄ alkoxy group and may optionally contain onedouble or triple bond; and R² is benzyl or C₁-C₆ alkyl which mayoptionally contain one double or triple bond, and wherein said C₁-C₆alkyl and the phenyl moiety of said benzyl may optionally be substitutedwith one fluoro, C₁-C₂ alkyl, C₁-C₂ alkoxy or chloro group.
 3. Acompound according to claim 1 wherein R³ is methyl, ethyl, chloro ormethoxy; R⁶ R⁸ and R⁹ are selected, independently, from hydrogen andmethyl; R⁵ is di- or tri-substituted phenyl, pyridyl, or pyrimidyl, inwhich up to three of the substitutents can be selected, independently,from C₁-C₄ alkyl, —O—(C₁-C₄ alkyl) and (C₁-C₂alkylene)—O—(C₁-C₄ alkyl),and wherein one of the substituents can be selected, independently, fromtrifluoromethyl, trifluoromethoxy, —CHO, (C₁-C₄ alkyl)—OH, cyano,chloro, fluoro, bromo, iodo and nitro, and wherein each of the foregoing(C₁-C₄) alkyl groups may optionally contain one double or triple bond;and Z is oxygen or NH.
 4. A compound according to claim 1 wherein A isCH.
 5. A compound according to claim 1 that is selected from:1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylicacid methyl ester;1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylicacid isopropyl ester;1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine;and1-(1-ethyl-propyl)-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-[1,6]-naphthyridin-2-one.6. A compound according to claim 2 wherein B is CHR¹R².
 7. A compoundaccording to claim 2 wherein B is NR¹R².
 8. A compound according toclaim 6 wherein R³ is methyl, ethyl, chloro, or methoxy.
 9. A compoundaccording to claim 7 wherein R³ is methyl, ethyl, chloro, or methoxy.10. A compound according to claim 8 wherein A is CH.
 11. A compoundaccording to claim 9 wherein A is CH.
 12. A compound according to claim8 wherein D is N; B—K—G is CR⁶═CH—C(═O), CR⁶R¹²—CH⁸—CHR⁸, orC(═O)—CR⁸═CR⁸.
 13. A compound according to claim 12, wherein CR⁶R¹² isCH₂ and CR⁶ is CH.
 14. A compound according to claim 12, wherein CHR⁸ isCH₂ and CR⁸ is CH.
 15. A compound according to claim 12, wherein CR⁶R¹²is CH₂, CR⁶ is CH CHR⁸ is CH₂ and CR⁸ is CH.
 16. A compound according toclaim 15, wherein R⁵ is di- or tri-substituted phenyl, pyridyl, orpyrimidyl, in which the two or three substituents are independentlyselected from C₁-C₄ alkyl, O—(C₁-C₄ alkyl), (C₁-C₂ alkylene)—O—(C₁-C₄alkyl), trifluoromethyl, trifluoromethoxy, CH(═O), (C₁-C₄ alkyl)—OH,chloro, fluoro, bromo, iodo, and nitro, and wherein each of theforegoing (C₁-C₄ alkyl) groups may optionally contain one double ortriple bond.
 17. A compound according to claim 2 wherein B is NR¹R², orCHR¹R²; and the ring containing D,E,K and G is a pyrido ring.
 18. Acompound according to claim 2, wherein B is NR¹R², CHR¹R²; and D—E—K—Gis C═CH—C(═O)—NH, or C═CH—C(═O)—NMe.
 19. A compound according to claim17, wherein R⁵ is di- or tri-substituted phenyl, in which the two orthree substituents are independently selected from C₁-C₄ alkyl, O—(C₁-C₄alkyl), (C₁-C₂ alkylene)—O—(C₁-C₄ alkyl), trifluoromethyl,trifluoromethoxy, CH(═O), (C₁-C₄ alkyl)—OH, chloro, fluoro, bromo, iodo,and nitro, and wherein each of the foregoing (C₁-C₄ alkyl) groups mayoptionally contain one double or triple bond.
 20. A compound accordingto claim 18, wherein R⁵ is di- or tri-substituted phenyl, in which thetwo or three substituents are independently selected from C₁-C₄ alkyl,O—(C₁-C₄ alkyl), (C₁-C₂ alkylene)—O—(C₁-C₄ alkyl), trifluoromethyl,trifluoromethoxy, CH(═O), (C₁-C₄ alkyl)—OH, chloro, fluoro, bromo, iodo,and nitro, and wherein each of the foregoing (C₁-C₄ alkyl) groups mayoptionally contain one double or triple bond.